The present invention relates to a crystalline form of the compound (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl] propanoic acid as shown in formula I below 
or a pharmaceutically-acceptable salt thereof, and solvates thereof. The invention also concerns methods of treating one or more metabolic disease conditions, particularly those associated with Insulin Resistance Syndrome, and the use of a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof, in the manufacture of a medicament for therapeutic use in one or more of said metabolic diseases.
The invention further concerns pharmaceutical compositions containing a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof, as active ingredient, as well as processes for the manufacture of a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof.
In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of subsequent manufacture of pharmaceutical formulations comprising the active compound.
Chemical stability, solid state stability, and shelf life of the active ingredients are also very important factors. The drug substance, and compositions containing it, should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component""s physico-chemical characteristics (e.g. its chemical composition, density, hygroscopicity and solubility).
Moreover, it is also important to be able to provide drug in a form which is as chemically-pure as possible.
Amorphous materials may present significant problems in this regard. For example, such materials are typically more difficult to handle and to formulate than crystalline material, provide for unreliable solubility, and are often found to be unstable and chemically impure.
The skilled person will appreciate that, if a drug can be readily obtained in a stable crystalline form, the above problems may be solved.
Thus, in the manufacture of commercially viable, and pharmaceutically acceptable, drug compositions, it is desirable, wherever possible, to provide drug in a substantially crystalline, and stable, form.
It is to be noted, however, that this goal is not always achievable. Indeed, typically, it is not possible to predict, from molecular structure alone, what the crystallisation behaviour of a compound will be, and this can usually only be determined empirically.
The above compound is intended for therapeutic use in Insulin Resistance Syndrome (IRS), which refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinaemia, possible type 2 diabetes mellitus, arterial hypertension, central (visceral) obesity, dyslipidaemia observed as deranged lipoprotein levels typically characterised by elevated VLDL (very low density lipoproteins) and reduced HDL (high density lipoproteins) concentrations and reduced fibrinolysis.
Recent epidemiological research has documented that individuals with insulin resistance run a greatly increased risk of cardiovascular morbidity and mortality, notably suffering from myocardial infarction and stroke. In type 2 diabetes mellitus atherosclerosis related conditions cause up to 80% of all deaths.
In clinical medicine there is awareness of the need to increase the insulin sensitivity in IRS suffering patients and thus to correct the dyslipidaemia which is considered to cause the accelerated progress of atherosclerosis. However, currently this is not a universally well defined disease.
The present invention relates to a crystalline solid form of the compound of formula I. Significant advantages can arise when the compound of formula I can be isolated in a crystalline form, for example, in the manufacture of the compound to the purity levels and uniformity required for regulatory approval and for ease and uniformity of formulation.
We have isolated the compound of formula I as a crystalline solid. The particular crystalline form isolated exists in a form which is substantially or essentially free of solvent (hereinafter referred to as xe2x80x9cthe anhydrous formxe2x80x9d). Alternatively a solvated form may be produced, for example, a hydrated form.
We present as a feature of the invention a crystalline form of a compound of formula I, or a solvate thereof. In an alternative feature of the invention we present a crystalline form of a pharmaceutically-acceptable salt of the compound of formula I, or a solvate thereof.
By the use of the term xe2x80x9csolvatedxe2x80x9d we also include hydrated. By the use of the term xe2x80x9ca crystalline formxe2x80x9d we mean each and everyone possible crystalline form of the compound of formula I, preferably an anhydrous form.
A crystalline form of the compound of formula I can be defined by reference to its melting point, powder X-ray diffraction pattern and single-crystal X-ray data.
The melting point of the crystalline form of the compound of formula I generally depends on the level of purity and may be determined by conventional procedures well known in the art, for example, by differential scanning calorimetry (DSC). Typically, the anhydrous form has a melting point which is in the range 82-92xc2x0 C., for example about 85-89xc2x0 C.
The anhydrous form has an X-ray powder diffraction pattern containing specific peaks of high intensity at 6.2, 4.47 and 4.15 xc3x85. Additional specific peaks of lower relative intensity to the first peaks are at 4.69, 3.64, 3.60 and 3.45 xc3x85.
A crystalline form of a compound of formula I may be obtained from a non-crystalline form of a compound of formula I, by crystallisation from a suitable solvent (including organic solvents, aqueous solutions and mixtures thereof), such as toluene and ethyl acetate, or a mixture of solvents, such as a mixture of ethanol/water, isopropanol/water or toluene/isooctane. To initiate crystallisation seeding with crystalline compound of formula I may be required. Crystallisation of the compound from an appropriate solvent system may be achieved by attaining supersaturation, for example, by cooling, by solvent evaporation and/or by the addition of an anti-solvent (a solvent in which the compound of formula I is poorly soluble, examples of suitable anti-solvents include heptane or isooctane). Crystallisation temperatures and times will vary depending upon the concentration of the compound of formula I in solution, the solvent system used and the method of crystallisation adopted.
A crystalline form of the compound of formula I may be isolated using techniques well known to those skilled in the art, for example, by decanting, filtration or centrifuging. Similarly the crystalline form may be dried in accordance with well known procedures.
Optional recrystallisation step(s) may be performed using the same or different solvent systems to reduce further impurities, such as amorphous material, chemical impurities, or to convert the crystalline form into a solvated/hydrated form or an anhydrous form.
Preferably crystallisation is carried out directly from the reaction solution. Alternatively crystallisation is performed from a subsequent solution.
A further feature of the invention is a process for the production of a crystalline form of a compound of formula I which comprises crystallising the compound of formula I.
By the use of the term xe2x80x9cthe anhydrous formxe2x80x9d, we do not exclude the presence of some solvent, including water, within the crystal lattice structure. Solvent, including water, may also be present outside the crystal lattice structure.
A feature of the invention is a crystalline form of a compound of formula I, as described above, for use in medical therapy.
According to a further feature of the invention there is provided a pharmaceutical composition which comprises a crystalline form of a compound of formula I, as described above, in association with a pharmaceutically-acceptable diluent or carrier. The use of a crystalline form of a compound of formula I, as described above, in the preparation of a pharmaceutical composition by bringing into association a crystalline form of a compound of formula I with a pharmaceutically-acceptable diluent or carrier.
The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension.
In general the above compositions may be prepared in a conventional manner using conventional excipients.
The amount of the crystalline form of a compound of formula I, as described above, that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.001 mg to 50 mg of active agent mixed with an appropriate and convenient amount of excipient(s) which may vary from about 10 to about 99.9999 percent by weight of the total composition.
The invention also includes the use of the crystalline compound of the invention, as described above in the production of a medicament for use in:
(i) treating dyslipidaemia;
(ii) treating type 2 diabetes mellitus;
(iii) treating hyperglycaemia;
(iv) treating hyperinsulinaemia;
(v) treating hyperlipidaemia;
(vi) treating arterial hypertension; and/or
(vii) treating abdominal obesity.
The invention also includes a method of producing an effect as defined hereinbefore or treating a disease or disorder as defined hereinbefore which comprises administering to a warm-blooded animal, preferably a human, requiring such treatment an effective amount of a crystalline form of a compound of formula I, as described above.
The size of the dose for therapeutic or prophylactic purposes of a crystalline form of a compound of formula I will naturally vary according to the nature and severity of the medical condition, the age and sex of the animal or patient being treated and the route of administration, according to well known principles of medicine.
Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001-50 mg/kg body weight, preferably 0.01-10 mg/kg body weight.
A crystalline form of the compound of formula I may be administered as a sole therapy or it may be administered in conjunction with other pharmacologically active agents such as a anti-diabetic, anti-hypertensive, diuretic or anti-hyperlipidaemic agent.
Crystalline forms prepared in accordance with the Example(s) below showed essentially the same powder X-ray diffraction patterns and/or DSC thermograms. It was clear when comparing the relevant patterns/thermograms (allowing for experimental error) that the same crystalline form had been formed. DSC onset temperatures may vary in the range xc2x15xc2x0 C. (for example xc2x12xc2x0 C.), and powder X-ray diffraction pattern distance values may vary in the range xc2x15 on the last decimal place.
Abbreviations
EtOAc=ethyl acetate
HPLC=high-pressure liquid chromatography
i-PrOAc=isopropyl acetate
NMP=N-methyl-2-pyrrolidinone
THF=tetrahydrofuran